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1.
J Exp Med ; 218(9)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34259830

RESUMO

Transforming growth factor-ß (TGFß) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFß signaling in myofibroblast differentiation: TGFß induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFß. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.

2.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204585

RESUMO

In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, n = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients (n = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (YAP1, PELI1, FGF2, VEGFA, KLF4) and matrix remodelling factors (MMP2, MMP9, TIMP1, TIPM2) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, KLF4, PELI1 and YAP1 were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, YAP1, PELI1, FGF2, TIMP2 and MMP9 were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified KLF4 as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/metabolismo , MicroRNAs/genética , Interferência de RNA , RNA Mensageiro/genética , Artérias Temporais/metabolismo , Biomarcadores , Biópsia , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Arterite de Células Gigantes/diagnóstico , Humanos , Imuno-Histoquímica , Avaliação de Sintomas , Artérias Temporais/patologia , Ultrassonografia
3.
Swiss Med Wkly ; 151: w20528, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34283895

RESUMO

OBJECTIVES: Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. METHODS: We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. RESULTS: We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. CONCLUSION: This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.

4.
BMJ Open ; 11(6): e048541, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168032

RESUMO

INTRODUCTION: In the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture 'Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)'. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc. METHODS AND ANALYSES: We aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating). ETHICS AND DISSEMINATION: This protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published. TRIAL REGISTRATION NUMBER: NCT04300426; Pre-results. PROTOCOL VERSION: V.3.1.


Assuntos
Microbioma Gastrointestinal , Escleroderma Sistêmico , Anaerobiose , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Transplante de Microbiota Fecal , Humanos , Los Angeles , Estudos Multicêntricos como Assunto , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Escleroderma Sistêmico/terapia , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-34146098

RESUMO

OBJECTIVE: Digital pitting scars (DPS) are frequent, but little studied in SSc to date. METHODS: An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to 1) examine DPS prevalence, 2) whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene), and 3) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with 1) functional impairment, 2) structural microvascular disease, 3) and mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia, and mortality. RESULTS: 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P = <0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P = <0.001) and joint synovitis (P = <0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (OR) with DUs: 22.03 (19.51 to 24.87), active digital ischaemia: 6.30 (5.34 to 7.42), and death: 1.86 (1.48 to 2.36). CONCLUSION: DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimise the therapeutic strategy.

6.
FASEB J ; 35(7): e21695, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34160101

RESUMO

Chronic wounds are a major disease burden worldwide. The breach of the epithelial barrier facilitates transition of skin commensals to invasive facultative pathogens. Therefore, we investigated the potential effects of Staphylococcus aureus (SA) on dermal fibroblasts as key cells for tissue repair. In co-culture systems combining live or heat-killed SA with dermal fibroblasts derived from the BJ-5ta cell line, healthy individuals, and patients with systemic sclerosis, we assessed tissue repair including pro-inflammatory cytokines, matrix metalloproteases (MMPs), myofibroblast functions, and host defense responses. Only live SA induced the upregulation of IL-1ß/-6/-8 and MMP1/3 as co-factors of tissue degradation. Additionally, the increased cell death reduced collagen production, proliferation, migration, and contractility, prerequisite mechanisms for wound closure. Intracellular SA triggered inflammatory and type I IFN responses via intracellular dsDNA sensor molecules and MyD88 and STING signaling pathways. In conclusion, live SA affected various key tissue repair functions of dermal fibroblasts from different sources to a similar extent. Thus, SA infection of dermal fibroblasts should be taken into account for future wound management strategies.


Assuntos
Fibroblastos/patologia , Dermatopatias Infecciosas/patologia , Pele/patologia , Infecções Estafilocócicas/complicações , Staphylococcus aureus/patogenicidade , Cicatrização , Adulto , Idoso , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Fibroblastos/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pele/microbiologia , Dermatopatias Infecciosas/microbiologia , Infecções Estafilocócicas/microbiologia , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-33989387

RESUMO

OBJECTIVE: To estimate the extent of and the reasons for ineligibility in randomized controlled trials (RCTs) of systemic sclerosis (SSc) patients included in the EUSTAR database, and to determine the association between patient's features and generalizability of study results. METHODS: We searched Clinicaltrials.gov for all records on interventional SSc-RCTs registered from January 2013 to January 2018. Two reviewers selected studies, and information on the main trial features were retrieved. Data from 8046 patients having a visit in the EUSTAR database since 2013 were used to check patient's eligibility. The proportion of potentially eligible patients per trial, and the risk factors for ineligibility were analyzed. Complete-, worst- and best-case analyses were performed. RESULTS: Of the 37 RCTs included, 43% were conducted in Europe, 35% were industry-funded, and 87% investigated pharmacological treatments. Ninety-one percent of 8046 patients included could have participated in at least one RCT. In complete-case analysis, the median [range] proportion of eligible patients having the main organ complication targeted by each study was 60% [10-100] in the overall sample of trials, ranging from 50% [32-79] for trials on skin fibrosis to 90% [34-77] for those targeting Raynaud's phenomenon. Among the criteria checked, treatment- and safety-related but not demographic were the main barriers to patient's recruitment. Older age, absence of Raynaud's phenomenon, and lower mRSS were independently associated with the failure to fulfill criteria for any of the included studies. CONCLUSIONS: Patient's representativeness in SSc-RCTs is highly variable and is driven more by treatment- and safety-related rather than demographic criteria.

8.
Arthritis Rheumatol ; 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34042326

RESUMO

OBJECTIVES: Little is known on the disease course of very early systemic sclerosis (SSc). It is unknown whether anti-centromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. We aim to evaluate whether ACA-IgG, -IgM and -IgA levels in ACA-IgG positive patients associate with disease severity and/or progression from very early SSc to definite SSc. METHODS: ACA-IgG positive patients with very early SSc and ACA-IgG positive patients fulfilling the 2013 ACR/EULAR criteria for SSc from five different cohorts were included. A diagnosis of very early SSc was based on the presence of ACA-IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling the 2013 ACR/EULAR criteria. Multivariable regression analyses were performed to determine the association between baseline isotype levels and progression to SSc and organ involvement. RESULTS: Six hundred twenty-five ACA-IgG positive patients were included of whom 138 (22%) fulfilled very early SSc criteria and 487 (78%) had definite SSc. ACA-IgG (Odds Ratio (OR) 2.5 (1.8-3.7)) and ACA-IgM (OR 1.8 (1.3 -2.3)) levels were significantly higher in definite SSc patients. Of 115 very early SSc patients with follow-up, 48 (42%) progressed to definite SSc within five years. Progression to definite SSc was associated with higher ACA-IgG levels at baseline (OR 4.3 (1.7-10.7)). CONCLUSION: ACA isotype levels might serve as a biomarker to identify very early SSc patients at risk for progression to definite SSc.

9.
Infect Control Hosp Epidemiol ; : 1-7, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33952361

RESUMO

OBJECTIVE: Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care. DESIGN: Prospective surveillance study during 2 influenza seasons. SETTING: Tertiary-care hospital. PARTICIPANTS: Volunteer sample of inpatients on medical wards and healthcare workers (HCWs). METHODS: Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission. RESULTS: In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals. CONCLUSIONS: Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.

10.
Eur Spine J ; 2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1168984

RESUMO

PURPOSE: The aim of this study was to investigate the effect of working from home on neck pain (NP) among office workers during the COVID-19 pandemic. METHODS: Participants from two Swiss organisations, aged 18-65 years and working from home during the lockdown (n = 69) were included. Baseline data collected in January 2020 before the lockdown (office work) were compared with follow-up data in April 2020 during lockdown (working from home). The primary outcome of NP was assessed with a measure of intensity and disability. Secondary outcomes were quality of workstation ergonomics, number of work breaks, and time spent working at the computer. Two linear mixed effects models were fitted to the data to estimate the change in NP. RESULTS: No clinically relevant change in the average NP intensity and neck disability was found between measurement time points. Each working hour at the computer increased NP intensity by 0.36 points (95% CI: 0.09 to 0.62) indicating strong evidence. No such effect was found for neck disability. Each work break taken reduced neck disability by 2.30 points (95% CI: - 4.18 to - 0.42, evidence). No such effect was found for NP intensity. There is very strong evidence that workstation ergonomics was poorer at home. CONCLUSION: The number of work breaks and hours spent at the computer seem to have a greater effect on NP than the place of work (office, at home), measurement time point (before COVID-19, during lockdown) or the workstation ergonomics. Further research should investigate the effect of social and psychological factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04169646. Registered 15 November 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646 .

11.
Arthritis Res Ther ; 23(1): 125, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888149

RESUMO

BACKGROUND AND OBJECTIVES: The University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) is validated to capture gastrointestinal (GI) tract morbidity in patients with systemic sclerosis (SSc). The aims of this study were to determine in a large SSc cohort if the UCLA GIT 2.0 is able to discriminate patients for whom a rheumatologist with experience in SSc would recommend an esophago-gastro-duodenoscopy (EGD), and if it could identify patients with endoscopically proven esophagitis or with any pathologic finding on EGD. METHODS: We selected patients fulfilling the ACR/EULAR 2013 criteria for SSc from our EUSTAR center having completed at least once the UCLA GIT 2.0 questionnaire, and we collected data on gastrointestinal symptoms and EGD from their medical charts. We analyzed by general linear mixed effect models several parameters, including UCLA GIT 2.0, considered as potentially associated with the indication of EGD, as well as with endoscopic esophagitis and any pathologic finding on EGD. RESULTS: We identified 346 patients (82.7% female, median age 63 years, median disease duration 10 years, 23% diffuse cutaneous SSc) satisfying the inclusion criteria, who completed UCLA GIT 2.0 questionnaires at 940 visits. EGD was recommended at 169 visits. In multivariable analysis, UCLA GIT 2.0 and some of its subscales (reflux, distention/bloating, social functioning) were associated with the indication of EGD. In 177 EGD performed in 145 patients, neither the total ULCA GIT 2.0 score nor any of its subscales were associated with endoscopic esophagitis, nor with any pathologic EGD findings. CONCLUSIONS: In a real-life setting, the UCLA GIT 2.0 and its reflux subscale were able to discriminate patients with SSc who had an indication for EGD, but did not correlate with findings in EGD. We conclude that, while using the UCLA GIT 2.0 in the routine care of patients with SSc may help the rheumatologist to better understand the burden of GI symptoms in the individual patient, it should not be used as a stand-alone instrument to identify an indication of EGD.


Assuntos
Gastroenteropatias , Escleroderma Sistêmico , Técnicas de Apoio para a Decisão , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Trato Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Inquéritos e Questionários
12.
Clin Exp Rheumatol ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33886453

RESUMO

OBJECTIVES: To evaluate the feasibility, validity, reliability, and responsiveness of the Hospital Anxiety and Depression Scale (HADS) and to analyse its model structure in patients with systemic sclerosis (SSc). METHODS: In this study, 316 systemic sclerosis patients were included; of these, 159 participated in the responsiveness analysis. Psychometric properties were tested in analogy to the Outcome Measures in Rheumatology (OMERACT) filter and an exploratory and confirmatory factor analysis was performed to examine the structure of HADS. RESULTS: The HADS showed adequate feasibility, validity, reliability, and responsiveness to clinically relevant worsening of the disease. For our population of SSc patients, the HADS model with two sub-scales, HADS-A and HADS-D, and a general scale HADS-S, measuring anxiety, depression, and distress, respectively, was most appropriate. The rates of anxiety, depression, mixed anxiety-depressive disorder (MADD) and distress identified by HADS were 32.2%, 25.9%, 18.5%, and 49.5%, respectively, in our cohort. CONCLUSIONS: The psychometric properties of the HADS make it useful for screening in SSc, where anxiety, depression, MADD, and distress represent a significant burden to patients.

13.
Eur Spine J ; 30(6): 1699-1707, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33817763

RESUMO

PURPOSE: The aim of this study was to investigate the effect of working from home on neck pain (NP) among office workers during the COVID-19 pandemic. METHODS: Participants from two Swiss organisations, aged 18-65 years and working from home during the lockdown (n = 69) were included. Baseline data collected in January 2020 before the lockdown (office work) were compared with follow-up data in April 2020 during lockdown (working from home). The primary outcome of NP was assessed with a measure of intensity and disability. Secondary outcomes were quality of workstation ergonomics, number of work breaks, and time spent working at the computer. Two linear mixed effects models were fitted to the data to estimate the change in NP. RESULTS: No clinically relevant change in the average NP intensity and neck disability was found between measurement time points. Each working hour at the computer increased NP intensity by 0.36 points (95% CI: 0.09 to 0.62) indicating strong evidence. No such effect was found for neck disability. Each work break taken reduced neck disability by 2.30 points (95% CI: - 4.18 to - 0.42, evidence). No such effect was found for NP intensity. There is very strong evidence that workstation ergonomics was poorer at home. CONCLUSION: The number of work breaks and hours spent at the computer seem to have a greater effect on NP than the place of work (office, at home), measurement time point (before COVID-19, during lockdown) or the workstation ergonomics. Further research should investigate the effect of social and psychological factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04169646. Registered 15 November 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646 .


Assuntos
COVID-19 , Cervicalgia , Ergonomia , Humanos , Cervicalgia/epidemiologia , Pandemias , SARS-CoV-2 , Suíça/epidemiologia
14.
Front Psychol ; 12: 620307, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1125423

RESUMO

Purpose: The COVID-19 lockdown interrupted normal daily activities, which may have led to an increase in sedentary behavior (Castelnuovo et al., 2020). The aim of this study was to investigate the effect of the COVID-19 pandemic on the level of physical activity among Swiss office workers. Methods: Office workers from two Swiss organizations, aged 18-65 years, were included. Baseline data from January 2020 before the COVID-19 pandemic became effective in Switzerland were compared with follow-up data during the lockdown phase in April 2020. Levels of physical activity were assessed using the International Physical Activity Questionnaire. Paired sample t-tests or Wilcoxon signed-rank test were performed for statistical analysis. Results: Data from 76 participants were analyzed. Fifty-four participants were female (71.1%). The mean age was 42.7 years (range from 21.8 to 62.7) at baseline. About 75% of the participants met the recommendations on minimal physical activity, both before the COVID-19 pandemic and during the lockdown. Weak statistical evidence for a decline in total physical activity in metabolic equivalent of task minutes per week (MET min/week) was found (estimate = -292, 95% CI from - ∞ to 74, p-value = 0.09), with no evidence for a decrease in the three types of activity: walking (estimate = -189, 95% CI from - ∞ to 100, p-value = 0.28), moderate-intensity activity (estimate = -200, 95% CI from - ∞ to 30, p-value = 0.22) and vigorous-intensity activity (estimate = 80, 95% CI from - ∞ to 460, p-value = 0.74). Across the three categories "high," "moderate," and "low" physical activity, 17% of the participants became less active during the lockdown while 29% became more active. Conclusion: The COVID-19 pandemic did not result in a reduction in total physical activity levels among a sample of Swiss office workers during the first weeks of lockdown. Improved work-life balance and working times may have contributed to this finding. Clinical Trial Registration: www.ClinicalTrials.gov, NCT04169646. Registered 15 November 2019 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33769468

RESUMO

OBJECTIVES: Study aim was to evaluate estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with mortality in systemic sclerosis (SSc) patients from the European Scleroderma Trials and Research Group (EUSTAR) database. METHODS: SSc patients from the EUSTAR database with available items for calculation of eGFR at baseline visit and with a second follow-up visit were included. A cut-off of 60 ml/min was chosen for all SSc patients and 30 ml/min for scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the role of eGFR as predictive factor of mortality. RESULTS: 3650 SSc patients were included. Mean serum level of creatinine and eGFR were 0.8 mg/dl (IQR 0.6-0.9) and 86.6 ± 23.7 ml/min. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR <60 ml/min respect to patients with eGFR ≥ 60 ml/min [OS at five years 0.763 (CI 95%: 0.700-0.814) vs 0.903 (CI 95%: 0.883-0.919 p< 0.001)]. In multivariable analysis, OS was associate with male gender (p< 0.01), systolic pulmonary arterial pressure (sPAP) (p< 0.001) and eGFR (p< 0.001). Cumulative incidence of deaths due to SSc was associate with increased sPAP (p< 0.001) and reduced eGFR (p< 0.05). OS at five years of 53 SRC patients was not significantly different in SSc patients with eGFR > 30 ml/min or eGFR < 30 ml/min. CONCLUSION: eGFR represents a predictive risk factor of overall survival in SSc. The eGFR is not a risk factor for death in SRC.

16.
Arthritis Rheumatol ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760395

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is characterised by dysregulation of type I interferon (IFN-I) signalling. CD52 is known for its immunosuppressive functions in T-cells. We aimed to investigate the role of CD52 in monocyte adhesion and IFN-I signalling in SSc. METHODS: Transcriptome profiles of circulating CD14+ monocytes from lcSSc, dcSS and healthy controls were analysed by RNA sequencing. Levels of CD52, CD11b/integrin αΜ and CD18/integrin ß2 in whole blood was assessed by flow cytometry. CD52 expression was analysed in relation to disease phenotype (early, lcSSc, dcSS) and autoantibody profiles. The impact of overexpression, knockdown, and antibody blocking of CD52 were analysed by gene and protein expressions and functional assays. RESULTS: Pathway enrichment analysis indicated an increase in adhesion- and IFN-I-related genes in SSc monocytes. These cells displayed up-regulated CD11b/CD18, reduced CD52 expression and enhanced adhesion to ICAM1 and endothelial cells. CD52 expression was consistent with SSc subtypes, immunosuppressive treatment and autoantibody profiles of SSc patients and monocyte adhesion properties. Overexpression of CD52 decreased CD18 levels and monocyte adhesion, while knockdown of CD52 increased monocyte adhesion. Treatment with the anti-CD52 antibody Alemtuzumab increased monocyte adhesion, CD11b/CD18 expression, and enhanced IFN-I responses. Monocytic CD52 expression was up-regulated by IL-4/IL-13 via STAT6 pathway and down-regulated by LPS, IFN-α, IFN-ß or IFN-γ in JAK1 and histone deacetylates (HDAC) IIa-dependent manner. CONCLUSIONS: Down-regulation of anti-adhesive CD52 antigen in CD14+ monocytes represents a novel mechanism in the pathogenesis of SSc. Targeting of the IFN-HDAC-CD52 axis in monocytes might represent a new therapeutic option for early SSc patients.

17.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668422

RESUMO

BACKGROUND: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. METHODS AND RESULTS: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-ß. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-ß-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. CONCLUSION: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-ß-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.


Assuntos
Fibroblastos/metabolismo , Antígeno 2 Relacionado a Fos/metabolismo , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de Transcrição AP-1/metabolismo , Idoso , Animais , Feminino , Fibroblastos/patologia , Fibrose , Antígeno 2 Relacionado a Fos/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Miocárdio/patologia , Fator de Transcrição AP-1/genética
18.
Front Psychol ; 12: 620307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688857

RESUMO

Purpose: The COVID-19 lockdown interrupted normal daily activities, which may have led to an increase in sedentary behavior (Castelnuovo et al., 2020). The aim of this study was to investigate the effect of the COVID-19 pandemic on the level of physical activity among Swiss office workers. Methods: Office workers from two Swiss organizations, aged 18-65 years, were included. Baseline data from January 2020 before the COVID-19 pandemic became effective in Switzerland were compared with follow-up data during the lockdown phase in April 2020. Levels of physical activity were assessed using the International Physical Activity Questionnaire. Paired sample t-tests or Wilcoxon signed-rank test were performed for statistical analysis. Results: Data from 76 participants were analyzed. Fifty-four participants were female (71.1%). The mean age was 42.7 years (range from 21.8 to 62.7) at baseline. About 75% of the participants met the recommendations on minimal physical activity, both before the COVID-19 pandemic and during the lockdown. Weak statistical evidence for a decline in total physical activity in metabolic equivalent of task minutes per week (MET min/week) was found (estimate = -292, 95% CI from - ∞ to 74, p-value = 0.09), with no evidence for a decrease in the three types of activity: walking (estimate = -189, 95% CI from - ∞ to 100, p-value = 0.28), moderate-intensity activity (estimate = -200, 95% CI from - ∞ to 30, p-value = 0.22) and vigorous-intensity activity (estimate = 80, 95% CI from - ∞ to 460, p-value = 0.74). Across the three categories "high," "moderate," and "low" physical activity, 17% of the participants became less active during the lockdown while 29% became more active. Conclusion: The COVID-19 pandemic did not result in a reduction in total physical activity levels among a sample of Swiss office workers during the first weeks of lockdown. Improved work-life balance and working times may have contributed to this finding. Clinical Trial Registration: www.ClinicalTrials.gov, NCT04169646. Registered 15 November 2019 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646.

19.
Invest Radiol ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33787538

RESUMO

PURPOSE: The aim of this study was to assess the accuracy and impact of different sizes and tube voltages on bone mineral density (BMD) assessment using a computed tomography (CT) topogram acquired with photon-counting detector CT in an osteopenic ex vivo animal spine. MATERIALS AND METHODS: The lumbar back of a piglet was used to simulate osteopenia of the lumbar spine. Five fat layers (each with a thickness of 3 cm) were consecutively placed on top of the excised spine to emulate a total of 5 different sizes. Each size was repeatedly imaged on (A) a conventional dual-energy x-ray absorptiometry scanner as the reference standard, (B) a prototype photon-counting detector CT system at 120 kVp with energy thresholds at 20 and 70 keV, and (C) the same prototype system at 140 kVp with thresholds at 20 and 75 keV. Material-specific data were reconstructed from spectral topograms for B and C. Bone mineral density was measured for 3 lumbar vertebrae (L2-L4). A linear mixed-effects model was used to estimate the impact of vertebra, imaging setup, size, and their interaction term on BMD. RESULTS: The BMD of the lumbar spine corresponded to a T score in humans between -4.2 and -4.8, which is seen in osteoporosis. Averaged across the 3 vertebrae and 5 sizes, mean BMD was 0.56 ± 0.03, 0.55 ± 0.02, and 0.55 ± 0.02 g/cm2 for setup A, B, and C, respectively. There was no significant influence of imaging setup (P = 0.7), simulated size (P = 0.67), and their interaction term (both P > 0.2) on BMD. Bone mineral density decreased significantly from L2 to L4 for all 3 setups (all P < 0.0001). Bone mineral density was 0.59 ± 0.01, 0.57 ± 0.01, and 0.52 ± 0.02 g/cm2 for L2, L3, and L4, respectively, for setup A; 0.57 ± 0.02, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup B; and 0.57 ± 0.01, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup C. CONCLUSION: A single CT topogram acquired on photon-counting detector CT with 2 energy thresholds enabled BMD quantification with similar accuracy compared with dual-energy x-ray absorptiometry over a range of simulated sizes and tube voltages in an osteopenic ex vivo animal spine.

20.
Chest ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33581097

RESUMO

BACKGROUND: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. RESEARCH QUESTION: Which factors determine the outcome of PH in COPD? STUDY DESIGN AND METHODS: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). RESULTS: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. INTERPRETATION: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov.

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